The compounds of this invention are enol acylate analogs of E.sub.1 and E.sub.2 prostaglandin derivatives.
Natural prostaglandins are alicyclic compounds related to prostanoic acid, the structure of which is: ##STR1## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of (I) is the trans-orientation of the side chains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. In (I), as elsewhere in this specification, solid lines ( ) provide a reference plane (such as the cyclopentyl ring or the bonds among C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20); a dashed line ( ) indicates projection of a covalent bond below such reference plane (alpha-configuration); while a wedge line ( ) represents projection above such plane (beta-configuration). These conventions apply to all structural formulae subsequently discussed in this specification. In some structures, however, a swung dash or serpentine line ( ) denotes orientation of a covalent bond either above or below the plane of reference. The compounds of the present invention have a double bond at either the C.sub.8 -C.sub.9 position. When the double bond is at C.sub.8 -C.sub.9, the C.sub.7 -C.sub.8 bond is in the .alpha. configuration and the side chains are trans in relation to each other. When the double bond is at C.sub.9 -C.sub.10, the C.sub.7 -C.sub.8 bond will be in the reference plane.
Natural prostaglandins have the general structure, ##STR2## in which L and M may be ethylene or cis-vinylene radicals. Prostaglandins are characterized by the substituents on the cyclopentyl ring, the position of double bonds, if any, in the cyclopentyl ring and the number of double bonds in the side chains. When the cyclopentyl ring is fully saturated, carbonyl substituted at the 9-position and hydroxyl substituted at the 11-position, an E-class prostaglandin (PGE) is represented and when there is a single double bond in the sidechains, i.e., L and M in Formula (II) are ethylene, a type-I prostaglandin is represented. The naturally occurring E-class type 1 prostaglandin known as prostaglandin E.sub.1 or PGE.sub.1, is represented by the formula: ##STR3## When there is a double bond at C.sub.5 -C.sub.6, i.e., L in Formula (II) is cis-vinylene, prostaglandin E.sub.2 or PGE.sub.2 is depicted.
Recent research indicates that certain prostaglandins, including PGE.sub.1 and PGE.sub.2 and derivatives thereof, elicit biochemical and physiological effects in a variety of mammalian systems. For example, in rats, PGE.sub.1 increases the release of growth hormone and in sheep it has been found to inhibit ovarian progesterone secretion. In mice, PGE.sub.1 has been found to increase thyroid activity whereas in hyphosectomized rats it has been found to stimulate stereordogenisis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens and in the female reproductive system PGE.sub.1 compounds contract uterine smooth muscle. Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGE.sub.1 inhibits gastric secretion and, in most mammalian respiratory tracts, PGE compounds affect in vitro preparation of tracheal smooth muscle. The human lung normally contains PGE compounds; consequently some cases of bronchial asthma may involve an imbalance in the production or metabolism of these compounds.
In addition, prostaglandins are involved in certain hematic mechanisms in mammals. For example, PGE.sub.1 inhibits aggregation of blood platelets in vitro. In a variety of mammalian cardiovascular systems, PGE compounds are vasodilators by virtue of their action on vascular smooth muscle.
The various therapeutic uses for PGE.sub.2 compounds include induction of human labor, parturition, abortion, luteolysis, as human bronchodilators as well as many of those uses mentioned for PGE.sub.1 compounds.
Accordingly, it can be seen that prostaglandins and their analogs have broad clinical implications and research in this area continues in laboratories throughout the world.
The present invention involves 9-enol acylate derivatives of PGE.sub.1 and PGE.sub.2. Acyloxy prostaglandin analogs have been reported in U.S. Pat. Nos. 3,636,120; 3,723,528 and 4,105,792; however, C-9 enol acylated prostaglandin analogs have not been reported in the patent or scientific literature.
Floyd et al disclose in J.Org.Chem., 44,71 (1979) the utilization of the enol acetate (1) as an intermediate in the synthesis of 11-deoxy cyclopentenones (2) which were then transformed to 11-deoxy prostaglandins. ##STR4##
Davis et al report in J.Org.Chem., 44, 3755 (1979) the preparation of PGF.sub.2.alpha. via conjugate addition and regiospecific enolate trapping. Thus the enolate (3) was trapped with various synthons to yield C-8 carbon alkylated prostaglandin intermediates (4). Also stated in this paper was that the enolate (3) "should be effectively trapped with Me.sub.3 SiCl, acetic anhydride, CIPO(OEt).sub.2, acyl chlorides, aldehydes, and reactive Michael acceptors". The present invention demonstrates the efficient trapping with a few of these reagents at the C-9 oxygen but not at C-8. ##STR5##
Copending application Ser. No. 154,384 discloses 1-acyloxy-15-deoxy-16-hydroxy prostaglandin E.sub.1 analogs characterized by the formula: ##STR6## where R.sub.1 and R.sub.2 are straight or branched chain alkyl groups.